Peripheral T cell lymphoma, unspecified

What every physician needs to know:

Peripheral T cell lymphoma (PTCL) is an aggressive disease that most commonly presents in patients over the age of 60 with rapidly progressive lymphadenopathy, fevers, night sweats, and weight loss. Extranodal involvement, particularly of the skin and bone marrow, is common. Occasionally PTCL can have a more subacute presentation, and initial biopsies may be more suggestive of an inflammatory infiltrate than a malignant process.

If the suspicion for PTCL is high, serial biopsies should be repeated over time. The presence of a clonal T cell population does not always establish a diagnosis of PTCL, as clonal T cell populations can be found in infectious or rheumatologic conditions. Similarly, the absence of an identifiable T cell clone does not definitively rule out a diagnosis of PTCL.

Although potentially curable with chemotherapy, PTCL has a worse prognosis than diffuse large B cell lymphoma. Peripheral T cell lymphoma represents a broad range of histologies with PTCL, not otherwise specified (NOS) being one subgroup -- this is a common source of confusion.

Are you sure your patient has peripheral T cell lymphoma, not otherwise specified? What should you expect to find?

Patients with PTCL frequently present with signs and symptoms common in other aggressive lymphoid malignancies. Lymphadenopathy is a common presenting sign. The presence or absence of pain associated with enlarged lymph nodes is not a helpful diagnostic clue.

Occasionally patients have otherwise asymptomatic lymphadenopathy detected while having a routine physical examination or radiographic study for other indications. Fevers, night sweats, poor appetite, and weight loss are often present. Extranodal, particularly cutaneous, involvement is more common in PTCL than in aggressive B cell lymphomas and can manifest as skin rash or as signs or symptoms of underlying organ dysfunction, such as jaundice from liver dysfunction or dyspnea from pulmonary involvement.

Cytopenias from bone marrow involvement are also common. Patients with PTCL seem to be endogenously immunosuppressed, even before the initiation of chemotherapy, and some patients can present with varicella zoster or opportunistic infections such as Pneumocystis jirovecii.

Beware of other conditions that can mimic peripheral T cell lymphoma, not otherwise specified:

PTCL can be confused with a variety of infectious or rheumatologic diseases due to the presence of fevers and lymphadenopathy. Also, cutaneous involvement with PTCL can initially suggest a dermatologic or rheumatologic process. To further confuse matters, clonal T cell populations (as well as clonal B cell populations) are sometimes present in the lymph nodes or the peripheral blood of patients with rheumatologic or infectious conditions.

Otherwise healthy patients over the age of 60 can also sometimes have benign clonal T cell populations in the peripheral blood, which can lead to a misdiagnosis of PTCL. Such T cell clones are usually CD4+ and are not accompanied by lymphadenopathy or systemic symptoms. The presence of widespread adenopathy, the lack of empiric evidence of infection such as positive blood cultures, and a negative serologic evaluation for rheumatologic disease can often quickly exclude conditions that mimic lymphoma. Ultimately, however, tissue biopsy is mandatory to establish or exclude the diagnosis of PTCL.

Although PTCL is generally an aggressive disease, occasionally it can follow a subacute course and an initial biopsy may show atypical lymphocytes, but may not conclusively demonstrate PTCL. If the suspicion for PTCL is high, the clinician should biopsy multiple sites over time, to definitively exclude the diagnosis.

Cutaneous involvement with PTCL can be confused with primary cutaneous T cell lymphoma, particularly since patients with cutaneous T-cell lymphoma (CTCL) can have regional, reactive lymphadenopathy. Radiographic staging, physical examination, bone marrow biopsy, and/or lymph node biopsy can readily distinguish PTCL from CTCL, in the vast majority of cases. PTCL can be confused with other lymphomas that have a significant T cell infiltrate such as T cell/histiocyte rich diffuse large B cell lymphoma, especially since T cell lymphomas can also have a histiocytic infiltrate (formerly known as Lennert lymphoma).

Immunophenotyping, T cell receptor gene rearrangement studies, and immunoglobulin clonality studies can almost always differentiate PTCL from T cell rich diffuse large B cell lymphoma. The same is true for Hodgkin lymphoma, which can also have a significant, reactive T cell infiltrate.

Which individuals are most at risk for developing peripheral T cell lymphoma, not otherwise specified:

PTCL accounts for less than 10% of all cases of non-Hodgkin’s lymphoma diagnosed in North America and Western Europe. Approximately 6,000 new cases are diagnosed every year in the United States. Table I shows the relative frequency of various PTCL histologies.

Table I.

Relative frequency of various PTCL histologies

T cell lymphoma subtype

Incidence as a percentage of all lymphoma cases

Peripheral T cell lymphoma not otherwise specified (PTCL, NOS)

3.7%

Anaplastic T/null cell lymphoma (ALCL)

2.4%

Extranodal NK/T cell lymphoma, nasal type*

1.4%

Angioimmunoblastic T cell lymphoma (AITL)

1.2%

Other

<1%

Patients with chronic immune suppression from HIV infection or from immunosuppression post-organ transplantation may be at higher risk for PTCL, although the vast majority of post-transplant lymphoproliferative disorders are of B cell origin. Hepatitis B and hepatitis C infection may also be a risk factor for PTCL, as well as B cell lymphomas. Exposure to ultraviolet radiation may increase the risk of T cell lymphoma in people with certain polymorphisms of the vitamin D receptor, though these preliminary findings require verification. Solvent exposure and dietary meat intake do not appear to be risk factors for developing PTCL.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

An excisional lymph node biopsy is preferred to make the diagnosis. A core needle biopsy may be acceptable as long as there is enough tissue for histology, flow cytometry, cytogenetics, and gene rearrangement studies. A fine needle aspirate is almost always inadequate to establish the diagnosis. Biopsy of skin lesions and/or a bone marrow biopsy can also help establish the diagnosis. Useful laboratory tests include a complete blood count to assess for sequelae of bone marrow involvement such as anemia and thrombocytopenia. Occasionally circulating lymphoma cells will be visible on peripheral blood smear.

An elevated lactate dehydrogenase (LDH) is suggestive of lymphoma and impacts prognosis. A normal LDH does not rule out lymphoma, nor does an elevated LDH conclusively establish the diagnosis. HIV testing is important, since HIV is a risk factor for lymphoma and acute HIV infection can present with many of the same symptoms as PTCL including fever, weight loss, and lymphadenopathy.

A comprehensive metabolic profile is important to assess for renal and liver impairment as a result of mechanical obstruction of the ureters or biliary ducts respectively or from direct organ involvement with lymphoma. Impaired organ function can also affect chemotherapy selection and dosing. Hyperphosphatemia, hyperuricemia, hyperkalemia, and/or renal impairment can suggest spontaneous tumor lysis syndrome from PTCL.

PTCL, NOS most commonly expresses CD4 (T helper phenotype) and much less commonly CD8 (cytotoxic phenotype). Expression of both CD4 and CD8 is very rare. CD8 expression may impart a worse prognosis. Other T cell antigens such as CD2, CD3, CD5, and CD7 are variably expressed. Loss of expression of CD7 and/or CD5 is common and can help distinguish PTCL from a benign inflammatory infiltrate where both CD5 and CD7 are usually expressed.

Up to 50% of cases may express Epstein-Barr virus (EBV) in the tumor cells or infiltrating B cells. The pathophysiologic significance of this is unclear, though in some series EBV expression has been associated with a worse prognosis. There are no characteristic cytogenetic findings pathognomonic of PTCL, NOS and the majority will have complex karyotypic changes. The T cell receptor gene (TCR) is rearranged in 80 to 90% of cases. The alpha/beta phenotype is much more common than the gamma/delta TCR gene rearrangement.

There are histologic variants of PTCL with unclear significance. Lennert lymphoma is a CD8+ PTCL with extensive lymphoepitheliod infiltration. Unlike most CD8+ PTCL, the prognosis of this variant appears no worse than CD4+ PTCL. Recently a variant of PTCL, NOS with a T follicular helper cell phenotype has been described. This subtype may be more closely related to AITL rather than other cases of PTCL, NOS. The T follicular subtype of PTCL, NOS often has a t(5;9) affecting the ITK and SYK tyrosine kinases (although upregulation of SYK is also often seen in other PTCL subtypes).

Gene expression and molecular profiling has demonstrated significant heterogeneity amongst cases of PTCL and has led to the identification of potential therapeutic targets such as platelet derived growth factor alpha and NF-kappaB. PTCL, NOS is almost certainly a collection of biologically distinct diseases that remain to be further defined.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of peripheral T cell lymphoma, not otherwise specified?

If anthracycline based chemotherapy is planned, patients should have an assessment of left ventricular function by either echocardiogram or Multi Gated Acquisition Scan (MUGA) scan. A lumbar puncture for cell count, differential, cytology, flow cytometry, protein, and glucose is only necessary if there is clinical or radiographic evidence of central nervous system (CNS) involvement. Lumbar puncture is not otherwise warranted given that PTCL does not commonly affect the central nervous system.

Computed tomography (CT) scans of the chest, abdomen, and pelvis are useful, both for establishing the diagnosis and staging the extent of lymphoma. Widespread or bulky adenopathy is more suggestive of lymphoma than carcinoma, infectious, or inflammatory conditions. Positron emission tomography (PET) scanning is not generally helpful in making the diagnosis, since inflammatory conditions and other cancers that present in a similar fashion to PTCL will often be fluorodeoxyglucose (FDG) avid. PET can be useful as a baseline to assess disease burden and during and immediately after treatment to assess response, though this remains to be validated. CT scans of the neck are optional but most disease in the neck can be followed adequately by palpation. CT or magnetic resonance imaging (MRI) of the head/brain is only necessary if there are signs or symptoms of CNS involvement.

If you decide the patient has peripheral T cell lymphoma, not otherwise specified, what therapies should you initiate immediately?

Once the diagnosis of PTCL is definitively established, patients should initiate chemotherapy unless they have comorbidities that preclude chemotherapy administration. If patients are very symptomatic, corticosteroids such as prednisone or dexamethasone can be initiated in the interval between the diagnostic biopsy and the receipt of the results.

Before initiating corticosteroids in this setting, the clinician must be confident that enough tissue was obtained for the pathologist to perform all necessary tests to establish the diagnosis, since corticosteroids could obscure the results of a future biopsy if the initial biopsy did not yield sufficient material to establish a diagnosis.

If the patient has signs of active tumor lysis syndrome they should be hydrated and initiated on allopurinol. In rare circumstances, rasburicase may be necessary if the uric acid is very high. A general guideline would be to consider rasburicase if the initial uric acid is over 10, or if there is evidence of uric acid induced nephropathy, such as an otherwise unexplained elevation in creatinine in the presence of hyperuricemia.

More definitive therapies?

T cell lymphomas are rare diseases and most treatment paradigms are extrapolated from the more common aggressive B cell lymphomas. Patients should be encouraged to participate in well designed clinical trials if available.

Outside of a clinical trial, most patients are treated with anthracycline based chemotherapy. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) given every 3 weeks for six cycles is the most commonly used regimen. CHOP can be given every 2 weeks but there is no definitive evidence that this schedule improves the treatment outcome in PTCL. Studies of more aggressive regimens such as HyperCVAD (fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone), MegaCHOEP (dose-escalated CHOP plus etoposide), and VIP-reinforced-ABVD (etoposide, ifosfamide, Cisplatin alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine) have not demonstrated superior outcomes to CHOP.

A retrospective analysis of a German trial of aggressive lymphomas, including PTCL, suggested that the addition of etoposide to CHOP (CHOEP) may improve outcome in patients under the age of 60 with a normal LDH. It is reasonable to utilize CHOEP in this patient population, though the results have not been confirmed in a randomized, prospective trial and are contradicted by a German trial showing no benefit to MegaCHOEP. Patients with localized stage I or II disease should be considered for involved field radiotherapy after six cycles of anthracycline based (CHOP or CHOEP) chemotherapy.

Abbreviated chemotherapy (three cycles) followed by radiotherapy has not been validated in early stage disease the way such an approach has been evaluated in diffuse large B cell lymphoma. Thus, six cycles of chemotherapy prior to radiotherapy is preferred.

Phase II studies have evaluated a number of other agents in combination with CHOP, including denileukin diftitox and alemtuzumab. Currently these combinations are being tested in randomized trials, but these agents should not routinely be added to CHOP until the results of those trials are known. A trial of bevacizumab in combination with CHOP for the initial treatment of T cell lymphoma was stopped early due to excessive toxicity, particularly cardiac toxicity.

Post-remission therapy

The poor response rate with anthracycline based chemotherapy in PTCL has generated intense interest in developing new, more effective treatment strategies. Based upon the success of high dose chemotherapy and autologous stem cell transplantation (ASCT) in relapsed/refractory B cell malignancies, similar strategies have been utilized in PTCL. The utility of ASCT in PTCL needs to be considered separately as part of the upfront (that is, planned) therapeutic regimen and as a strategy for relapsed/refractory disease.

One of the largest published experiences with autologous transplant in PTCL was published by the Spanish Gel-Tamo group. This trial retrospectively analyzed 115 patients undergoing high dose therapy and ASCT between January 1990 and December 1999. Of these, 37 were in first complete remission (CR), 28 were in second or subsequent CR, 44 were in partial remission (PR), and six had refractory disease. As a group, the 5 year disease free survival was 60%, with a 5 year overall survival (OS) of 56%. However, patients transplanted in first CR had a 5 year overall survival of 80% which was statistically significantly higher than those patients transplanted in second or subsequent CR or PR.

No patient with refractory disease was a long term disease free survivor. Retrospective analyses from several other groups confirmed that autologous transplantation was most beneficial in first CR, relative to second or subsequent CR or PR.

As a result of seemingly improved long-term disease free and overall survival observed retrospectively with ASCT in first PR or CR, several groups initiated prospective trials incorporating ASCT into the frontline treatment regimen. A German group reported on 83 patients treated between 2000 and 2006. Of these, 32 patients had PTCL, NOS and 27 had AITL. On intent to treat analysis, 66% of patients completed the entire study treatment, with 55 of the 83 patients undergoing ASCT. The most common reason for not undergoing ASCT was progressive disease (24 patients).

The 3 year OS in this study was 48%. Notably, there was significantly better survival in the group of patients with a low Prognostic Index for PTCL (PIT) score compared to those with a high PIT score. This does raise the question as to whether or not the autologous transplant was truly beneficial, or whether these favorable risk patients would have done well with chemotherapy alone.

Allogeneic stem cell transplant (alloSCT) has also been studied in PTCL, primarily in the relapsed/refractory setting. One of the most widely cited alloSCT trials in PTCL was published by Corradini and colleagues and utilized reduced intensity conditioning. This study included mostly patients with a related donor. The 5 year progression free survival (PFS) for the study population as a whole was an impressive 49%, with a 5 year OS of 54%. The risk of non-relapse mortality was 20%. Two retrospective studies from the European Bone Marrow Transplant Registry confirmed the efficacy of alloSCT in PTCL. In a study of 91 PTCL patients undergoing alloSCT after reduced intensity conditioning, the 5 year PFS was 39% and 5 year OS was 43%. The non-relapse mortality was substantial at 29%.

The net result of these studies is that the role of stem cell transplantation in T cell lymphoma remains undefined. Most data would suggest that autologous transplantation is most effective in first remission or at least in complete remission, regardless of the line of therapy. Studies of allogeneic transplantation have demonstrated a significant proportion of long-term disease free survivors but at a significant rate of transplant related mortality. Also, not all patients will have available donors and a substantial number of patients with PTCL will be precluded from allogeneic transplant due to age and/or comorbidities.

Randomized trials are ongoing, in which patients are assigned to allogeneic transplant or autologous transplant in first remission, depending on donor availability. Until the results of these trials are known, it is reasonable to offer appropriate patients autologous transplantation in first remission, reserving allogeneic transplantation for patients whose disease recurs after autologous transplantation or who require multiple chemotherapy regimens to achieve an initial remission.

Management of relapsed/refractory disease

Patients who fail to achieve an initial CR or who relapse after an initial CR require salvage therapy if their medical condition otherwise permits. As with upfront treatment, patients should be offered participation in well designed clinical trials, since the optimal therapy in this setting remains undefined. The only drug specifically approved by The Food and Drug Administration (FDA) to treat relapsed/refractory PTCL is the antifolate pralatrexate, which has a response rate of 27% with a median duration of response of just over 9 months.

In a subgroup analysis PTCL, NOS had the highest response rate at approximately 40%. However, in patients with an adequate performance status and hematologic reserve, combination therapy should be considered prior to single agent therapy. Gemcitabine is a particularly active drug in PTCL and is often combined with platinum drugs (increasingly oxaliplatin, though historically cisplatin) with or without corticosteroids. Other traditional lymphoma salvage regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP) can also be utilized. Pentostatin has a response rate of approximately 20% in PTCL and is well tolerated.

Patients who have failed a prior autologous transplantation who subsequently remit should be offered allogeneic transplantation if they are suitable candidates and a donor is available. Patients who did not undergo autologous transplant in first remission and who subsequently enter a complete remission should be offered autologous transplantation, although the data is conflicting as to whether or not autologous transplantation is beneficial in this setting. Allogeneic transplantation may be preferable for patients who fail to achieve a CR with salvage therapy, even if they have not undergone a prior autologous transplant. Transplantation of any kind is less effective in the setting of refractory disease and generally should not be offered if a patient is not responding to salvage chemotherapy.

A number of agents are currently being studied or have been studied in relapsed/refractory PTCL. These include the histone deacetylase inhibitors, romidepsin and belinostat, the fusion protein denileukin diftitox, the anti-CD52 antibody alemtuzumab, and the anti-CD4 antibody zanolimumab. None however are yet approved by the FDA for this indication.

What other therapies are helpful for reducing complications?

Pegfilgrastim or filgrastim are useful in most patients receiving combination chemotherapy to decrease the chance of febrile neutropenia. Patients with a high disease burden or elevated uric acid should be initiated on allopurinol for the first 10 to 14 days of the first cycle of chemotherapy and should be monitored for tumor lysis syndrome. Rarely, rasburicase may be necessary if the patient has severe spontaneous or treatment induced tumor lysis syndrome and/or renal compromise. Patients receiving pralatrexate require folic acid and vitamin B12 supplementation. Patients receiving trimethoprim/sulfamethoxazole or probenecid conncomitantly with pralatrexate may be at increased risk of pralatrexate induced toxicity and should be monitored closely or have the drugs held if it is safe to do so.

What should you tell the patient and the family about prognosis?

PTCL is potentially curable with chemotherapy. The median progression free survival (PFS) following CHOP chemotherapy is 12 to 14 months. Approximately 20 to 30% of patients will be alive, and disease free, 5 years after the completion of treatment. The International Prognostic Index (IPI) was developed to predict outcome in diffuse large B cell lymphoma. The scale assigns one point to each of the five potential risk factors: age greater than 60, ECOG (Eastern Cooperative Oncology Group) performance status greater than two, elevated serum LDH, more than one extranodal site of involvement, and stage III or IV disease (the IPI risk factors can be remembered by the mnemonic APLES (Age, Performance status, LDH, Extranodal sites, and Stage). The IPI also predicts outcome in PTCL. Table II shows the 5 year OS by IPI score for PTCL.

Table II.

Five year overall survival by IPI score for PTCL

IPI

5 year overall survival

0 to 1

74%

2

49%

3

21%

4 to 5

6%

Unfortunately, a higher proportion of patients with PTCL will present with a high IPI score relative to aggressive B cell lymphoma patients, thus resulting in the overall poorer outcome seen with PTCL as a group, relative to aggressive B cell non-Hodgkin lymphoma (NHL) as a group.

Recently, a separate prognostic index for PTCL (Prognostic Index for T-cell lymphoma: PIT) has been proposed. This model is quite similar to the IPI but includes only four factors: age greater than 60, performance status of two or greater, increased LDH, and bone marrow involvement. Substantively these factors do not differ substantially from those identified in the IPI. Table III shows the outcome by PIT score.

Table III.

Five year overall survival by PIT score for PTCL

PIT Score

5 year OS

10 year OS

0

62%

55%

1

53%

39%

2

33%

18%

3-4

18%

12%

Substantively, there is a significant amount of overlap between the IPI and the PIT. Neither of these systems has emerged as the clear standard, though at present most clinicians and authors most widely cite the IPI.

"What if" scenarios.

In general, dose density and dose intensity matter in potentially curable lymphomas including PTCL. Every attempt should be made to maintain chemotherapy at full dose and on time.

Patients with PTCL may present with high fevers and a sepsis-like clinical picture. If a thorough search for infectious causes is unrevealing, chemotherapy can be initiated in this setting, as treating the lymphoma will often reverse these symptoms.

Pathophysiology

PTCL, NOS is a heterogeneous group of histologies that does not fulfill diagnostic criteria for one of the other more specific subgroups of T cell lymphoma. Most cases of PTCL, NOS derive from activated CD4+ T cells. CD8+ PTCL, NOS (called the cytotoxic phenotype) is less common, but seems to have a worse prognosis.

Gene expression profiling has identified upregulation of genes involved in proliferation, cell adhesion, matrix remodelling, and apoptosis. Over expression of platelet derived growth factor alpha and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) have also been identified and may represent important therapeutic targets. NF-kappaB expression may indicate a better prognosis, though this needs to be verified in larger, prospective studies.

What other clinical manifestations may help me to diagnose peripheral T cell lymphoma, not otherwise specified?

Occasionally, PTCL can be associated with hemophagocytic syndrome (HPS) (although this has been more classically associated with primary cutaneous gamma-delta T cell lymphoma). HPS is characterized by cytokine dysregulation that results in massive, systemic T cell and histiocyte activation. Patients typically present with fevers, rash, hepatosplenomegaly, lymphadenopathy, and neurologic changes such as delirium.

What other additional laboratory studies may be ordered?

Females of reproductive age should undergo a serum or urine pregnancy test if chemotherapy is contemplated, since most chemotherapeutics are teratogenic, particularly if given in the first trimester.

Males should be counseled about sperm banking and warned that many men will be transiently infertile as a result of the disease itself, especially if they have "B" symptoms such as night sweats and unintentional weight loss.

[Most recent series examining the use of gene expression profiling as a diagnostic and categorical tool in T cell lymphoma, replicating similar work done in diffuse large B cell lymphoma Primary Therapy.]

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